Abstract Primate lentiviruses have become highly adapted to their respective natural hosts and species- specific variations in host proteins that are required for or that inhibit lentivirus replication limit their tropism. This has protected humans from cross-species transmissions but has also hindered the development of animal models for HIV-1. Investigating how primate lentiviruses interact with cell host proteins allow us to understand the changes required for these viruses to colonize a new species and potentially manipulate their tropism. The goals of this proposal are to determine the requirements in HIV-1 and SIV envelope glycoproteins (Envs) to efficiently use macaque CD4 without compromising their neutralization phenotype. This study will reveal the role of CD4 variation in shaping envelope glycoprotein (Env) adaptation during lentiviral transmission between primates and impact the development of viruses with expanded tropism that will be useful in macaque models for AIDS.